Many human health problems, including birth defects and cancer result from a breakdown in normal developmental controls. The long term goal of this research is the understanding of the mechanisms controlling differentiation through the exploitation of the cellular slime mold as a developmental genetic model system. The specific aim for this period of support is to exploit the genetic system to study the role of cytoplasmic microtubules in cell differentiation. Microtubule deficiencies have been found to be associated with a number of human diseases including Duchenne muscular dystrophy, Alzheimers disease, Chediak-Higashi syndrome and Lesch-Nylan syndrome. Our particular approach is to analyze a large set of mutants that we have isolated, which are resistant to mitotic inhibitors. Through the use of biochemical, genetic, and biological experiments we will determine which of the mutants have defects in the microtubule system and how the different classes of mutants relate to each other. At the same time we will carry out biochemical studies to characterize the normal cellular cytoskeleton so that mutants can be compared with the wild type. We will also continue to study those mutants whose phenotypes already indicate that they are worthy of further study. We also plan to study in detail those mutants that are determined to be defective in the microtubular system. Lastly, we plan to use new selections to obtain further microtubule mutants.